The retinal ganglion cell is a retinal output cell, and its axon is also called an optic nerve fibers, runs in the retinal inner layer and the nerve fibers layer (nearest side to the vitreous body), gathers at the optic disc, leaves the eye ball, forms an optic nerve and undertakes a role of transmitting visual information to the cerebral cortex. Moreover, the retinal ganglion cell is distributed over the entire area of the retina. Accordingly, for example, a retinal damage due to inflammation and the like causes retinal neuropathy, retinal vascular occlusion, periphlebitis retinae, Eales' disease, ischemic ophthalmopathy, retinal arteriolar microaneurysm, retinopathy caused by hypertension, renal disease and blood disease, diabetic retinopathy, retinal dystrophy, macular dystrophy, chorioretinopathy, macular degeneration, macular edema, retinal pigment epithelium detachment, degenerative retinoschisis, retinoblastoma, retinal pigment epithelioma and the like, along with which a visual disorder occurs. Furthermore, degeneration and damage of the optic nerve causes the onset of optic neuritis, capillary angioma of optic disc, ischemic optic neuropathy, defects of retinal nerve fibers layer, retinal optic atrophy, neurotmesis of optic nerve, traumatic optic neuropathy, choked disc, coloboma of optic disc, optic nerve hypoplasia, toxic optic atrophy and the like, along with which a visual disorder occurs. It is further known that elevated intraocular pressure (glaucoma etc.) and the like cause atrophy and degeneration of the optic nerve, which in turn causes a visual disorder. For these visual disorders, a pharmaceutical agent capable of recovering the function of the visual information transmission pathway in the retina, particularly a pharmaceutical agent capable of neogenesis (regeneration) of the axon of retinal ganglion cell and promotion of extension thereof, and a pharmaceutical agent capable of neogenesis (regeneration) of the optic nerve cell are considered to be useful. While surgical efforts have been made in recent years such as retinal transplantation and retinal regeneration, in such efforts, too, it is highly useful to find a means and a pharmaceutical agent to promote neogenesis (regeneration) and extension of the optic nerve axon after transplantation.
On the other hand, as a compound having a Rho kinase inhibitory activity, a compound of the formula (I) to be mentioned later has been reported recently [WO98/06433 (corresponding patents: EP956865 and U.S. Pat. No. 6,218,410)]. Certain isoquinolinesulfonamide derivative and isoquinoline derivative are also reported to show a Rho kinase inhibitory activity (WO98/06433 and Naunyn-Schmiedeberg's Archives of Pharmacology 385(1) Suppl., R219, 1998). Furthermore, it has been reported that ethacrynic acid, certain vinyl benzene derivatives such as 4-[2-(2,3,4,5,6-pentafluorophenyl)-acryloyl]cinnamic acid and the like have a Rho kinase inhibitory activity [WO00/57914, JP-A-2000-44513 (corresponding patents: EP1094055 and U.S. Pat. No. 6,329,547)]. In addition, it has been reported that certain kinds of nitrogen-containing compounds, inclusive of N-[1-(3,5-dimethoxybenzyl)-tetrahydro-1H-3-pyrrolyl]-N-(1H-5-indazolyl)amine, have Rho kinase inhibitory activity (WO01/56988). It has been also reported that certain kinds of thiochroman compounds have Rho kinase inhibitory activity (WO01/68607).
The Rho kinase is a serin/threonine kinase activated along with the activation of Rho, and is known to function at the downstream of Rho and phosphorylate various substances, thereby controlling various physiological functions such as formation of stress fibers and desmosomes, contraction of smooth muscle, retraction of nerve axon and the like.
Inhibition of Rho kinase having such various physiological functions is considered to lead to the prophylaxis or treatment of various disease states, diseases and disorders. For example, as a pharmaceutical use of a compound having Rho kinase inhibitory activity, WO98/06433 widely discloses a therapeutic agent of hypertension, a therapeutic agent of angina pectoris, a cerebrovascular spasm suppressant, a therapeutic agent of asthma, a therapeutic agent of peripheral circulatory disturbance, a premature delivery preventive, a therapeutic agent of arterial sclerosis, an anticancer drug, an anti-inflammatory agent, an immunosuppressant, a therapeutic agent of autoimmune diseases, an anti-AIDS agent, a therapeutic agent of osteoporosis, a therapeutic agent of retinopathy, a cerebral function improver, a contraceptive drug, and a gastrointestinal tract infection preventive. In addition, WO01/56988 published after the earliest priority date of the present application describes that a specific compound having Rho kinase inhibitory activity is useful as a therapeutic agent of hypertension, asthma, angina pectoris, cerebrovascular contraction, peripheral circulation disorder, threatened abortion, glaucoma, tunnel vision, frequent urination, cancer, infiltration and metastasis of cancer, arteriosclerosis, retinopathy, immune response, inflammatory autoimmune disease, cerebral function disorder, osteoporosis, bacterial infection, chronic kidney failure, chronic nephritis, diabetic nephropathy, IgA nephropathy, a disease relating to the formation of thrombus, rheumatism, erectile dysfunction and fibrosis. Since it also has intraocular pressure lowering action, optic disc blood flow increasing action and aqueous humor outflow promoting action based on cilliary muscle relaxing action, its use as an agent for the prophylaxis or therapy of glaucoma has been reported [WO00/09162 (corresponding to EP1034793)]. WO00/57914 also describes its usefulness as an intraocular pressure lowering agent.
Furthermore, the compound of formula (I) has been already known to be useful as an agent for the prophylaxis or treatment of disorders of circulatory organs such as coronary, cerebral, renal, peripheral artery and the like (e.g., a therapeutic agent of hypertension, a therapeutic agent of angina pectoris, a therapeutic agent of renal and peripheral circulation disorder, a suppressive agent of cerebrovascular contraction and the like), which is potent and long lasting, and also as a therapeutic agent of asthma [JP-A-62-89679, JP-A-3-218356, JP-A-4-273821, JP-A-5-194401 (corresponding patents; EP641781 and U.S. Pat. No. 5,478,838), JP-A-6-41080 and WO95/28387 (corresponding patents; EP757038, U.S. Pat. No. 5,958,944 and U.S. Pat. No. 6,156,766)].
The isoquinolinesulfonamide derivative described in the above-mentioned WO98/06433 is known to be effective as a vasodilating agent, a therapeutic agent of hypertension, a cerebral function improver, an anti-asthma agent, a heart protecting agent, a platelet aggregation inhibitor, a therapeutic agent of neurologic manifestation, an anti-inflammatory agent, an agent for the prevention and treatment of hyperviscosity syndrome, a therapeutic agent of glaucoma, an intraocular pressure lowering agent, an improver of motor paralysis due to of cerebral thrombosis, an agent for prevention and treatment of virus infection and transcriptional control factor inhibitor [JP-A-57-200366, JP-A-61-227581, JP-A-2-256617, JP-A-4-264030, JP-A-6-56668 (corresponding patents; EP654266 and U.S. Pat. No. 5,747,507), JP-A-6-80569 (corresponding patent; WO94/05290), JP-A-6-293643, JP-A-7-41424, JP-A-7-277979, WO97/23222 (corresponding patents; EP868186 and U.S. Pat. No. 6,271,224), JP-A-9-227381, JP-A-10-45598 and JP-A-10-87491].
Moreover, the isoquinoline derivative described in the above-mentioned publication (Naunyn-Schmiedeberg's Archives of Pharmacology 385(1) Suppl., R219, 1998) is known to be useful as an agent for the prevention and treatment of brain tissue disorder due to vasospasm [WO97/28130 (corresponding patents; EP885888 and U.S. Pat. No. 6,153,608)].
However, there is no description disclosing that a compound having Rho kinase inhibitory activity has an action to improve visual function disorder or an action to improve visual function disorder caused by damage and/or degeneration of retinal nerve cell (the neural retina) or optic nerve (the nervus opticus), particularly an action to promote regeneration and extension of the axon of retinal ganglion cell.
The Rho-Rho kinase pathway is known to exhibit various functions in living organism as mentioned above, and involvement in the extension of nerve axon has been recently reported (The Journal of Cell Biology, vol. 141, 1625–1636 (1998), Neuron, 26, 431–441 (2000), The Journal of Neuroscience, vol. 19(17), 7537–7547 (1999)). However, none of them directly teaches the role of Rho kinase in retinal ganglion cell or the effect afforded by a Rho kinase inhibitor, and there is no description to suggest the usefulness of the Rho kinase inhibitor in the recovery of the visual function.